Antihistaminic piperidine derivatives and intermediates for the preparation thereof

ABSTRACT

This invention relates to novel compounds of formula:                    
     wherein 
     R 1  is H or C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched; 
     R 2  and R 3  are each independently C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched; or stereoisomers or pharmaceutically acceptable acid addition salt thereof.

RELATED U.S. APPLICATION DATA

This application is a divisional of U.S. patent application Ser. No.09/723,796 (filed Nov. 27, 2000), which is a continuation of U.S. patentapplication Ser. No. 09/344,024 (filed Jun. 25, 1999), now abandoned,which claimed benefit of provisional application 60/155,244 (filed Jul.2, 1998), which applications are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

This invention relates to novel piperidine derivatives of formula (I)and a process for the preparation thereof.

wherein

R₁ is H or C₁-C₆alkyl wherein the C₁C₆alkyl moiety is straight orbranched;

R₂ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbonatoms and is straight or branched; or

stereoisomers or pharmaceutically acceptable acid addition salt thereof.

Terfenadine,α-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol,is a known antihistaminic agent which is currently availablecommercially under the name Seldane® with a recommended dosage of 60 mgb.i.d. (See PHYSICIAN'S DESK REFERENCE, 52nd Edition, 1998,pp.1238-1244, Medical Economics Data, a division of Medical EconomicsCompany, Inc. Montvale, N.J.). Terfenadine is disclosed in U.S. Pat. No.3,878,217, issued Apr. 15, 1975. Sorken and Heel have provided a reviewof the pharmacodynamic properties and therapeutic efficacy ofterfenadine [Drugs 29, 34-56 (1985)].

Terfenadine undergoes extensive (99%) first pass metabolism to twoprimary metabolites (fexofenadine) and an inactive dealkylatedmetabolite. Fexofenadine, a.k.a.4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl-α,α-dimethyl-benzeneaceticacid, has been disclosed as an antihistaminic agent having oral activityin U.S. Pat. No.4,254,129, issued Mar. 3, 1981. It is currentlyavailable commercially under the name Allegra® (See PHYSICIAN'S DESKREFERENCE, 52nd Edition, 1998, pp.1189-1190, Medical Economics Data, adivision of Medical Economics Company, Inc. Montvale, N.J.).

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel piperidinederivatives of formula (I) useful for the treatment of allergicdisorders. It is a further object to provide a process for thepreparation of said derivatives and to provide novel intermediatesuseful for preparation of the same.

Additionally, it is an object of the present invention to provide amethod of treating a patient suffering from an allergic disordercomprising administering to said 10 patient an effective antiallergicamount of a compound of formula (I).

Furthermore, it is an object of the present invention to provide acomposition comprising an assayable amount of a compound of formula (I)in admixture or otherwise in association with one or morepharmaceutically acceptable carriers or excipients.

Another object of the present invention is to provide novel processesfor the preparation of intermediates useful for the synthesis offexofenadine and related compounds.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the formula (I) can be prepared using techniques andprocedures well known and appreciated by one of ordinary skill in theart.

As used herein, straight or branched alkyl groups having from 1 to 6carbon atoms as referred to herein are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and straight- andbranched-chain pentyl and hexyl.

The piperidine derivatives of the formula (I) can form pharmaceuticallyacceptable salts. Pharmaceutically acceptable acid addition salts of thecompounds of this invention are those of any suitable inorganic ororganic acid. Suitable inorganic acids are, for example, hydrochloric,hydrobromic, sulfuric, and phosphoric acids. Suitable organic acidsinclude carboxylic acids, such as, acetic, propionic, glycolic, lactic,pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic,ascorbic, maleic, hydroxymaleic, and dihydroxymaleic, benzoic,phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranillic, cinnamic,salicyclic, 4-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic, andmandelic acid, sulfonic acids, such as, methanesulfonic, ethanesulfonicand β-hydroxyethanesulfonic acid. Non-toxic salts of the compounds ofthe above-identified formula formed with inorganic or organic bases arealso included within the scope of this invention and include, forexample, those of alkali metals, such as, sodium, potassium and lithium,alkaline earth metals, for example, calcium and magnesium, light metalsof group IIIA, for example, aluminum, organic amines, such as, primary,secondary or tertiary amines, for example, cyclohexylamine, ethylamine,pyridine, methylaminoethanol and piperazine. The salts are prepared byconventional means, as for example, by treating a piperidine derivativeof formula (I) with an appropriate acid or base.

The novel process for preparing the piperidine derivatives of formula(I) is set forth in Scheme A. in Scheme A, R₁, and R₂ are C₁-C₆alkylwherein the C₁-C₆alkyl moiety is straight or branched; R₃ is H orC₁-C₆alkyl wherein the C₁-C₆alkyl moiety is straight or branched; and Xis Cl, Br or I.

Scheme A provides a general synthetic procedure for preparing thecompounds of formula (I).

In step A, a phenylacetyl halide (1) wherein X is Cl, Br, or I, isreacted with N-O-dimethylhydroxylamine hydrochloride to provideN-methoxy-N-methyl benzeneacetamide (2).

For example, a suitable phenylacetyl halide (1) is contacted with amolar excess of potassium carbonate in a suitable solvent such astoluene. Suitable phenylacetyl halides include phenylacetyl chloride,phenylacetyl bromide or phenylacetyl iodide. A preferred phenylacetylhalide is phenylacetyl chloride. A molar equivalent ofN-O-dimethylhydroxylamine hydrochloride dissolved in water is thenadded. The reaction mixture is stirred for a period of time ranging from1 to 24 hours at a temperature range of from 0° C. to 60° C. A preferredstirring time is 3 hours. A preferred temperature is 25° C.N-methoxy-N-methyl-benzeneacetamide is (2) is recovered from thereaction zone by extractive methods as are known in the art.

In step B, N-methoxy-N-methyl-benzeneacetamide (2) is acylated with asuitable 4-halo-substituted butyrylhalide of the formula

wherein each X is independently Cl, Br or I;

under Friedel-Crafts conditions to give a mixture of para, metasubstituted ω-halo-α-keto-benzeneacetamide (3). Surprisingly, the paraisomer is readily isolated by subsequent crystallization as set forth instep C.

For example, in step B, N-methoxy-N-methylbenzeneacetamide (2) iscontacted with suitable 4-halo-substituted butyrylhalide under thegeneral conditions of a Friedel-Crafts acylation using a suitable Lewisacid. Examples of suitable 4-halo-substituted butyrylhalides include4-chlorobutyrylchloride, 4-bromobutyrylbromide, and the like. Apreferred 4-halo-substituted butyrylhalide is 4 chlorobutyrylchloride.The reaction is carried out in a solvent, such as carbon disulfide,1,2-dichloroethane, n-hexane, acetonitrile, 1-nitropropane,nitromethane, diethyl ether, carbon tetrachloride, methylene chloride,tetrachloroethane or nitrobenzene with dichloromethane being thepreferred solvent. The reaction time varies from about ½ hour to 25hours at a temperature range of from 0° C. to 40° C. A preferredstirring time is 6 hours. A preferred temperature is 40° C. The mixtureof para, meta substituted ω-halo-α-keto-benzeneacetamide (3) isrecovered from the reaction zone by an aqueous quench followed byextractive methods as are known in the art.

Suitable Lewis acids for the acylation reaction described in step B arewell known and appreciated in the art. Examples of suitable Lewis acidsare boron trichloride, aluminum chloride, titanium tetrachloride, borontrifluoride, tin tetrachloride and zinc chloride. The selection andutilization of suitable Lewis acids for the acylation reaction of step Bis well known and appreciated by one of ordinary skill in the art.

The para-substituted ω-halo-α-keto-benzeneacetamide (3) is purified byrecrystallization techniques as set forth in step C.

For example, the product of the extractive methods as set forth in stepB is stirred in a suitable organic solvent such as a mixture ofheptane/ethyl acetate (ca. 4:1) and collected. The solid is dissolved ina suitable solvent such as ethyl acetate at a temperature range of from25° C. to 76° C. A preferred temperature is 76° C. The solution is thencontacted with charcoal. This mixture is then filtered and diluted witha suitable solvent such as heptane. The resultant slurry is then heateduntil a homogenous solution is obtained. Substantially purepara-substituted ω-halo-α-keto-benzeneacetamide (4) crystallizes uponstanding at room temperature.

In step D, the substantially pure para-substitutedω-halo-α-keto-benzeneacetamide (4) is hydrolyzed to give the4-(cyclopropylcarbonyl)benzeneacetic acid (5).

For example, the substantially pure para-substitutedω-halo-α-keto-benzeneacetamide (4) is contacted with a molar excess ofan appropriate base such as potassium hydroxide in a suitable solventsuch as ethanol. The reactants are typically stirred together for aperiod of time ranging from 1 to 24 hours at a temperature range of from0° C. to 78° C. A preferred stirring time is 18 hours. A preferredtemperature is 25° C. The 4-(cyclopropylcarbonyl)benzeneacetic acid (5)is recovered from the reaction zone by acidification and extractivemethods as are known in the art.

In step E, the 4-(cyclopropylcarbonyl)benzeneacetic acid (5) isesterified to give the corresponding4-(cyclopropylcarbonyl)benzeneacetic acid ester (6).

For example, the appropriate 4-(cyclopropylcarbonyl)benzeneacetic acid(5) is reacted with an excess of an appropriate C₁-C₆ alcohol which isstraight or branched in the presence of a catalytic amount of mineralacid, such as hydrochloric acid or sulfuric acid, hydrochloric acidbeing preferred, at a temperature range of from 25° C. to 78° C. Thereactants are typically stirred together for a period of time rangingfrom 2 to 72 hours. A preferred stirring time is 24 hours. A preferredtemperature is 25° C. The corresponding4-(cyclopropylcarbonyl)benzeneacetic acid ester (6) is recovered fromthe reaction zone by basification and extractive methods as are known inthe art. It can be purified by silica gel chromatography.

In step F, the appropriate 4-(cyclopropylcarbonyl)benzeneacetic acidester (6) is acylated with the appropriate acylating agent to give thecorresponding [4(cyclopropylcarbonyl)phenyl]propanedioic acid diester(7).

For example, the appropriate 4-(cyclopropylcarbonyl)benzeneacetic acidester (6) is reacted with a slight molar excess of a suitable acylatingagent. Suitable acylating agents include dialkylcarbonates, such as,dimethylcarbonate or diethylcarbonate; or chloroformates, such as,methyl chloroformate or ethyl chloroformate. The reaction is typicallyconducted in a suitable aprotic solvent in the presence of a suitablenon-nucleophilic base from about 0.5 hour to 7 days and at a temperatureof about 0° C. to the reflux temperature of the solvent. A preferredstirring time is 3 days. A preferred temperature is 25° C. Suitablesolvents for the acylation reaction include tetrahydrofuran, dioxane, ortert-butyl methyl ether. A preferred solvent is tetrahydrofuran.Suitable non-nucleophilic bases for the acylation reaction includeinorganic bases, for example, sodium bicarbonate, potassium bicarbonate,or hydrides, for example, sodium hydride or potassium hydride oralkoxides, for example, potassium tert-butoxide. A preferred base issodium bis(trimethylsilyl)amide.

The derivative formed upon acylation is optionally alkylated with asuitable alkylating agent in situ subsequent to the acylation. Suitablealkylating agents include alkyl halides, such as, iodomethane,chloromethane or bromomethane; or dialkylsulfates, such as,dimethylsulfate or diethylsulfate. The reactants are typically stirredtogether for a period of time ranging from 1 to 48 hours at atemperature range of from 0° C. to 30° C. A preferred stirring time is24 hours. A preferred temperature is 25° C.

The corresponding [4-(cyclopropylcarbonyl)phenyl]propanedioic aciddiester (7) is recovered from the reaction zone by extractive methods asare known in the art. It can be purified by silica gel chromatographyand/or recrystallization.

While not necessary for utilization in the acylation and subsequentalkylation in step F, the keto functionality of the4-(cyclopropylcarbonyl)benzeneacetic acid ester (6) may be protectedwith a suitable protecting group. The selection and utilization ofsuitable protecting groups for the keto group of structure (6) is wellknown by one of ordinary skill in the art and is described in“Protective Groups in Organic Synthesis”, Theodora W. Greene, Wiley(1981). For example, suitable protecting groups for the ketofunctionality include acyclic ketals such as dimethyl ketal; cyclicketals such as 1,3-dioxanes and 1,3-dioxalanes; acyclic dithioketalssuch as S,S-dimethyl ketal; cyclic dithio ketals such as 1,3-dithianeand 1,3-dithiolane derivatives; acyclic monothio ketals; cyclic monothioketals such as 1,3-oxathiolanes.

In step G, the appropriate [4-(cyclopropylcarbonyl)phenyl]propanedioicacid diester (7) is ring-opened to give the corresponding[4-(4-halo-1-oxobutyl)phenyl]propanedioic acid diester (8).

For example, the appropriate [4-(cyclopropylcarbonyl)phenyl]propanedioicacid diester (7) is contacted with a suitable hydrogen halide such ashydrogen chloride, hydrogen bromide, or hydrogen iodide in a suitableorganic solvent or in the absence of solvent. Suitable organic solventsinclude alcohol solvents, such as, ethanol, methanol, isopropyl alcohol,or n-butanol; hydrocarbon solvents, such as, benzene, toluene or xylene;halogenated hydrocarbons, such as chlorobenzene, chloroform or methylenechloride or dimethylformamide or acetic acid or dioxane at a temperaturerange of from 0° C. to 100° C. The absence of solvent is preferred. Thereactants are typically stirred together for a period of time rangingfrom 1 hour to 24 hours. A preferred stirring time is 4 hours to 16hours. A preferred temperature range is 60° C. to 80° C. If solvent ispresent, the [4-(4-halo-1-oxo-butyl)phenyl]propanedioic acid diester (8)is recovered from the reaction zone by extractive methods as are knownin the art and subsequent evaporation of the solvent.

In step H, the halo functionality of the appropriate[4-(4-halo-1-oxo-butyl)phenyl]propanedioic acid diester (8) is alkylatedwith α-(4-pyridyl)benzhydrol (commercially available from AldrichChemicals) to give the corresponding[4-[4-[4-(hydroxydiphenylethyl)-1-piperidinyl]1-oxobutyl]phenyl]propanedioicacid diester (9).

For example, the alkylation reaction is carried out in a suitablesolvent preferably in the presence of a non-nucleophilic base andoptionally in the presence of a catalytic amount of an iodide source,such as potassium or sodium iodide. The reaction time varies from about4 hours to 7 days and the reaction varies from about 25° C. to thereflux temperature of the solvent. A preferred stirring time is 3 days.A preferred temperature is the reflux temperature of the solvent.Suitable solvent for the alkylation reaction include alcohol solventssuch as, methanol, ethanol, isopropyl alcohol, or n-butanol; ketonesolvents, such as, methyl isobutyl ketone; hydrocarbon solvents, suchas, benzene, toluene or xylene, and mixtures thereof with water;halogenated hydrocarbons, such as, chlorobenzene or methylene chlorideor dimethylformamide. A preferred solvent is toluene/water (10:4).Suitable non-nucleophilic bases for the alkylation reaction includeinorganic bases, for example, sodium bicarbonate, potassium bicarbonate,or potassium carbonate or organic bases, such as, a trialkylamine, forexample, triethylamine, or pyridine, or an excess ofα-(4-pyridyl)benzhydrol may be used. A preferred base is potassiumcarbonate.

The corresponding[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]propanedioicacid diester (9) is recovered from the reaction zone by extractivemethods as are known in the art. It can be purified by silica gelchromatography.

While not necessary for the utilization in the alkylation of step H, theketo functionality of the [(4-halo-1-oxo-butyl)phenyl]propanedioic aciddiester (8) may be protected with a suitable protecting group. Theselection and utilization of suitable protecting groups for the ketogroup of structure (8) is well known by one of ordinary skill in the artand is described in “Protective Groups in Organic Synthesis”, TheodoraW. Greene, Wiley (1981). For example, suitable protecting groups for theketo functionality include acyclic ketals such as dimethyl ketal; cyclicketals such as 1,3-dioxanes and 1,3-dioxalanes; acyclic dithioketalssuch as S,S-dimethyl ketal; cyclic dithio ketals such as 1,3-dithianeand 1,3-dithiolane derivatives; acyclic monothio ketals; cyclic monothioketals such as 1,3-oxathiolanes.

In step I, the appropriate[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]propanedioicacid diester (9) is reduced selectively to the corresponding4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-benzeneaceticacid ester (10). This is accomplished by utilizing a suitable selectivereducing agent. A suitable selective reducing agent is a reagent orcombination of reagents which will selectively reduce only one ester ofthe propanedioic acid diester functionality to the correspondinghydroxymethyl moiety while not reducing the second ester of thepropanedioic acid diester functionality. Suitable selective reducingagents include lithium tri-tert-butoxyaluminohydride or the combinationof a suitable silane and a suitable titanocene-based catalyst.

For example, the appropriate[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]propanedioicacid diester (9) is contacted with a suitable selective reducing agentsuch as lithium tri-tert-butoxyaluminohydride in a suitable solvent suchas tetrahydrofuran, diethyl ether, or dioxane. A preferred solvent istetrahydrofuran. The reactants are typically stirred together for aperiod of time ranging from 0.5 hours to 168 hours at a temperaturerange of from 0° C. to 65° C. A preferred stirring time is 48 hours. Apreferred temperature is 25° C.

Catalytic reduction may also be employed in the preparation of4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-benzeneaceticacid ester (10) from an appropriate[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]propanedioicacid diester (9), using, for example, a suitable titanocene-basedcatalyst in which a suitable silane, such as, polymethylhydrosiloxane,serves as the stoichiometric reductant. Suitable titanocene-basedcatalysts include the active catalytic species commonly known as“Cp₂TiH”. It is well known by one of ordinary skill in the art that theactive catalytic species “Cp₂TiH” may be generated, for example, by theaddition of 2 equivalents of ethyl magnesium bromide to 1 equivalent ofCp₂TiCl₂ in a suitable solvent such as tetrahydrofuran.

For example, the catalytic reduction is carried out in a suitablesolvent such as tetrahydrofuran or diethyl ether or dioxane attemperatures ranging from about 25° C. to the reflux temperature of thesolvent. A preferred temperature for use with the catalytic reduction is65° C. The reaction time varies from about 8 hours to 24 hours. Apreferred stirring time is 18 hours. The4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-benzeneaceticacid ester (10) is recovered from the reaction zone after work-up withBu₄NF and utilization of extractive methods as are known in the art. Itcan be purified by silica gel chromatography.

In addition, a chiral catalytic reduction may also be employed in thepreparation of enantiomerically pure4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-benzeneaceticacid ester (10) from an appropriate[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]propanedioicacid diester (9), using an appropriate chiral titanocene system, suchas, for example, is described in Journal of the American ChemicalSociety, 116, 11667-11670 (1994).

As one skilled in the art would appreciate, the[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]propanedioicacid diester (9) wherein the keto group is protected must be reactedwith an appropriate deprotecting reagent prior to the reduction reactiondescribed in step I. The selection and utilization of appropriatedeprotecting reagents is well known by one of ordinary skill in the artand is described in “Protective Groups in Organic Synthesis”, TheodoraW. Greene, Wiley (1981). For example, cleavage of a dimethylketalprotecting group on the keto functionality of the[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]propanedioicacid diester (9) can be achieved by using iodotrimethylsilane or diluteacid as is known in the art.

In step J, the appropriate4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-benzeneaceticacid ester (10) is optionally hydrolyzed to the corresponding4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-benzeneaceticacid (11).

For example, hydrolysis may be achieved using methods known in the artsuch as potassium carbonate in methanol, methanolic ammonia, potassiumcarbonate, potassium hydroxide, calcium hydroxide, sodium hydroxide,magnesium hydroxide, sodium hydroxide/pyridine in methanol, potassiumcyanide in ethanol and sodium hydroxide in aqueous alcohols, with sodiumhydroxide being preferred. The reaction is typically carried out in anaqueous lower alcohol solvent, such as methanol, ethanol, isopropylalcohol, n-butanol, 2-ethoxyethanol or ethylene glycol or pyridine. Apreferred solvent is a mixture of tetrahydrofuran/methanol/water(3:2:1). The reaction is typically carried out at temperatures rangingfrom room temperature to the reflux temperature of the solvent. Apreferred temperature is 65° C. The reactants are typically stirredtogether for a period of time ranging from 1 to 24 hours. A preferredstirring time is 4 hours. The4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-benzeneaceticacid (11) is recovered from the reaction zone by acidification andextractive methods as are known in the art.

Of course it is understood that the compound of formula (I) may exist ina variety of stereoisomers. The compound has more than one chiralcenter. For example, the benzylic carbon to which the carboxyl,hydroxymethyl and methyl groups attach may exist in the (R) or the (S)form. In addition, the benzylic carbon to which the hydroxy, hydrogenand alkyl amino groups attach may exist in the (R) or the (S) form. Itis further understood that the present invention encompasses thosecompounds of formula (I) in each of their various structural and stereoisomeric configurations as individual isomers and as mixtures ofisomers.

An alternative novel process for the preparation of4-(cyclopropylcarbonyl)benzeneacetic acid is set forth in Scheme B. Thiscompound is useful for the synthesis of compounds of formula (I) as wellas fexofenadine and related compounds. In Scheme B, R₁ is C₁-C₆alkyl andthe C₁-C₆alkyl moiety is straight or branched.

In step a of Scheme B, the appropriate benzeneacetic acid ester (1)wherein R₁ is C₁-C₆alkyl and the C₁-C₆alkyl moiety is straight orbranched, is acylated with a suitable 4-halo-substituted butyrylhalideof the formula

wherein each X is independently Cl, Br, or I, under Friedel-Craftsconditions to give a mixture of the corresponding para, meta substitutedω-halo-α-keto-benzeneacetic acid ester (2) wherein X is Cl, Br, or I.

For example, in step a, the appropriate benzeneacetic acid ester (1) iscontacted with a 4-halo-substituted butyrylhalide under the generalconditions of a Friedel-Crafts acylation using a suitable Lewis acid.Examples of suitable 4-halo-substituted butyrylhalides include4-chlorobutyrylchloride, 4-bromobutyrylbromide, and the like. Apreferred 4-halo-substituted butyrylhalide is 4-chlorobutyrylchloride.The reaction is carried out in a solvent, such as carbon disulfide,1,2-dichloroethane, n-hexane, acetonitrile, 1-nitropropane,nitromethane, diethyl ether, carbon tetrachloride, methylene chloride,tetrachloroethane or nitrobenzene with dichloromethane being thepreferred solvent. The reaction time varies from about ½ hour to 25hours at a temperature range of from 0° C. to 40° C. A preferredstirring time is 6 hours. A preferred temperature is 40° C. The mixtureof para, meta substituted ω-halo-α-keto-benzeneacetic acid ester (2) isrecovered from the reaction zone by an aqueous quench followed byextractive methods as are known in the art.

Suitable Lewis acids for the acylation reaction described in step a arewell known and appreciated in the art. Examples of suitable Lewis acidsare boron trichloride, aluminum chloride, titanium tetrachloride, borontrifluoride, tin tetrachloride and zinc chloride. The selection andutilization of suitable Lewis acids for the acylation reaction of step ais well known and appreciated by one of ordinary skill in the art.

In step b of Scheme B, the mixture of meta- and para-substitutedω-halo-α-keto-benzeneacetic acid ester (2) is hydrolyzed to give amixture of meta- and para-substituted (cyclopropylcarbonyl)benzeneaceticacid (3).

For example, the mixture of meta- and para-substitutedω-halo-α-keto-benzeneacetic acid (2) is contacted with a molar excess ofan appropriate base such as lithium hydroxide or potassium hydroxide ina suitable solvent such as ethanol. The reactants are typically stirredtogether for a period of time ranging from 1 to 24 hours at atemperature range of from 0° C. to 78° C. A preferred stirring time is18 hours. A preferred temperature is 25° C. The meta- andpara-substituted (cyclopropylcarbonyl)benzeneacetic acid (3) isrecovered from the reaction zone by acidification and extractive methodsas are known in the art.

Surprisingly, the substantially pure para isomer is readily isolated bysubsequent crystallization as set forth in step c of Scheme B.

For example, the product of the extractive methods as set forth in stepb is dissolved in a suitable organic solvent such as a mixture ofheptane/ethyl acetate (ca. 4:1) with heating to reflux. The solution istreated with charcoal and filtered. Upon cooling, the resultant solid iscollected and recrystallized from a suitable organic solvent such asethyl acetate/heptane. Substantially pure para-substituted(cyclopropylcarbonyl)benzeneacetic acid (4) crystallizes upon standingat room temperature.

As shown previously herein, 4-(cyclopropylcarbonyl)benzeneacetic acidhas utility as an intermediate in the synthesis of compounds of formula(I). 4-(Cyclopropylcarbonyl)benzeneacetic acid may also be used as anintermediate in the process of preparing compounds of formula (7) asshown in Scheme C. Compounds of formula (7) include fexofenadine andrelated compounds.

In step a of Scheme C, the 4-(cyclopropylcarbonyl)benzeneacetic acid (1)is esterified to give the corresponding4-(cyclopropylcarbonyl)benzeneacetic acid ester (2) wherein R₁ isC₁-C₆alkyl and the C₁-C₆alkyl moiety is straight or branched, underconditions as set forth in Scheme A, Step E.

In step b of Scheme C, the 4-(cyclopropylcarbonyl)benzeneacetic acidester (2) is alkylated with a suitable alkylating agent to provide acorresponding alkylated [4-(cyclopropylcarbonyl)phenyl]benzeneaceticacid ester (3) wherein R₁ is as previously defined in step a and R₂ andR₃ are each independently C₁-C₆alkyl wherein the C₁-C₆alkyl moiety isstraight or branched.

For example, the reaction is typically conducted in a suitable aproticsolvent in the presence of a suitable non-nucleophilic base. Suitablesolvents for the alkylation reaction include diglyme, tetrahydrofuran,dioxane, or tert-butyl methyl ether. A preferred solvent is diglyme.Suitable non-nucleophilic bases for the alkylation reaction includesodium bis(trimethylsilyl)amide, inorganic bases, for example, sodiumbicarbonate, potassium bicarbonate, or hydrides, for example, sodiumhydride or potassium hydride or alkoxides, for example, potassiumtert-butoxide. A preferred base is potassium tert-butoxide. Suitablealkylating agents include alkyl halides, such as, iodomethane,chloromethane or bromomethane; or dialkylsulfates, such as,dimethylsulfate, or diethylsulfate. The reactants are typically stirredtogether for a period of time ranging from 1 to 48 hours at atemperature range of from 0° C. to 80° C.

In step c of Scheme C, the appropriate alkylated[4-(cyclopropylcarbonyl)phenyl]benzeneacetic acid ester (3) is ringopened to provide the corresponding [4-(4-halo-1-oxo-butyl)phenyl]benzene acetic acid ester (4) wherein R₁, R₂ and R₃ are as previouslydefined in step b and X is Cl, Br or I. The reaction occurs underconditions set forth in step G of Scheme A.

In step d, the appropriate [4-(4-halo-1-oxo-butyl)phenyl] benzene aceticacid ester (4) is alkylated with α-(4-pyridyl)benzhydrol to produce a[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxo-butyl]phenyl]benzeneaceticacid ester (5) wherein R₁, R₂ and R₃ are as previously defined in stepb, under conditions that were previously disclosed in U.S. Pat. No.4,254,129, the disclosure of which is herein incorporated by reference.

In step e of Scheme C, the appropriate[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]benzeneaceticacid ester (5) is reacted with a suitable reducing agent to produce a4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]benzeneaceticacid ester (6) wherein R₁, R₂ and R₃ are as previously defined in stepb, under conditions that were previously disclosed in U.S. Pat. No.4,254,129. Suitable reducing agents include, for example, sodiumborohydride or potassium borohydride. Catalytic reduction using, forexample, Raney nickel, palladium, platinum, or rhodium catalysts, mayalso be employed in step e of Scheme C.

In step f of Scheme C, the4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]benzeneaceticacid ester (6) is optionally hydrolyzed to produce the4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]benzeneaceticacid (7) wherein R₂ and R₃ are as previously defined in step b, underconditions that were previously disclosed in U.S. Pat. No. 4,254,129.

While not necessary for utilization in alkylation steps b and d, theketo functionality of the 4-(cyclopropylcarbonyl)benzeneacetic acidester (6) may be protected with a suitable protecting group. Theselection and utilization of suitable protecting groups for the ketogroup of structure (6) is well known by one of ordinary skill in the artand is described in “Protective Groups in Organic Synthesis”, TheodoraW. Greene, Wiley (1981). For example, suitable protecting groups for theketo functionality include acyclic ketals such as dimethyl ketal; cyclicketals such as 1,3-dioxanes and 1,3-dioxalanes; acyclic dithioketalssuch as S,S-dimethyl ketal; cyclic dithio ketals such as 1,3-dithianeand 1,3-dithiolane derivatives; acyclic monothio ketals; cyclic monothioketals such as 1,3-oxathiolanes.

The following examples present typical syntheses as described in SchemesA B and C. Starting materials for use in Schemes A, B and C are readilyavailable to one of ordinary skill in the art. These examples areunderstood to be illustrative only and are not intended to limit thescope of the present invention in any way. As used herein (throughoutthe specification), the following terms have the indicated meanings: “g”refers to grams; “mmol” refers to millimoles; “mL refers to milliliters;“bp” refers to boiling point; “mp” refers to melting point; “°C.” refersto degrees Celsius; “mm Hg” refers to millimeters of mercury; “μL”refers to microliters; “μg” refers to micrograms; and “μM” refers tomicromolar.

EXAMPLES OF SYNTHESIS SET FORTH IN SCHEME A

Step A: Preparation of N-Methoxy-N-methyl-benzeneacetamide

Dissolve potassium carbonate (100 g, 720 mmol) in water (100 mL). Add asolution of phenylacetyl chloride (50 g, 320 mmol) in toluene (250 mL).Then add a solution of N-O-dimethylhydroxylamine hydrochloride (32 g,330 mmol) in water (100 mL) dropwise over one hour. After three hours,carefully add 10% hydrochloric acid (250 mL) and tert-butyl methyl ether(125 mL). Separate the organic phase, wash with 10% hydrochloric acidand saturated sodium hydrogen carbonate solution. Dry over anhydrousmagnesium sulfate and concentrate to give the title compound (55 g,95%).

Step B: Preparation of [4-(4-Chloro-1-oxobutyl)]-N-methoxy-N-methylbenzeneacetamide

Cool a slurry of aluminum chloride (87 g, 650 mmol) in methylenechloride (100 mL) with an ice bath. Add 4-chlorobutyryl chloride (51 g,360 mL) dropwise over 0.5 hours. Add N-methoxy-N-methyl-benzeneacetamide(53 g, 300 mmol) over 0.5 hours. Allow the resultant solution to warm toroom temperature. Then heat at reflux for 6 hours. Cool the solution toroom temperature. Pour the solution into ice (1 L) and add methylenechloride (1 L). Separate the organic phase. Extract the aqueous phasewith methylene chloride (2×500 mL). Dry the combined organics overanhydrous magnesium sulfate and concentrate to provide a solid whichcontains a ca. 1:1 mixture of the title compound and the meta isomer.

Step C: Crystallization of[4-(4-Chloro-1-oxobutyl)]1-N-methoxy-N-methyl-benzeneacetamide

Slurry the solid obtained in step B in heptane/ethyl acetate (ca. 4:1)and then collect it. Dissolve the solid in hot ethyl acetate and treatthe resultant solution with ca. 5 g of charcoal. Filter throughdiatomaceous earth and add heptane (60 mL). Heat the slurry until ahomogenous solution is obtained. Allow the solution to stand overnightat room temperature. Filter the resultant crystalline solid and washwith heptane to provide purified[4-(4-chloro-1-oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide (20 g).Allow the mother liquor to stand for 5 days and collect a second crop ofthe crystalline solid (3.0 g) to obtain a total of 23 g (28%) of thepurified [4-(4-chloro-1-oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide.

Step D: Preparation of 4-(Cyclopropylcarbonyl)benzeneacetic acid

Add purified[4-(4-chloro-1-oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide (9.4 g,330 mmol) to a solution of potassium hydroxide (22.0 g) in ethanol (160mL). Stir 18 hours. Pour the solution into dilute hydrochloric acid (30mL of concentrated hydrochloric acid in 500 mL of water). Extract thesolution with three 500-mL portions of ethyl acetate. Dry the combinedorganic phases over anhydrous magnesium sulfate and concentrate to givethe title compound (6.4 g, 95%).

Step E: Preparation of 4-(cyclopropylcarbonyl) benzeneacetic acid, ethylester

Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid in ethanol (150 mL)containing concentrated sulfuric acid (10 drops). Stir 24 hours. Addtriethylamine (2 mL) and concentrate the solution. Dissolve the residuein water/ethyl acetate. Wash the organic phase with saturated sodiumhydrogen carbonate solution, dry over anhydrous magnesium sulfate andconcentrate. Purify by silica gel chromatography (400 mL silica gel, 20%ethyl acetate/heptane as eluent) to give the title compound (7.0 g,88%).

Step E: Preparation of 4-(cyclopropylcarbonyl)benzeneacetic acid, methylester

Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid in methanol (100 mL)containing concentrated sulfuric acid (10 drops). Stir 24 hours. Addtriethylamine (2 mL) and concentrate the solution. Dissolve the residuein water/ethyl acetate. Wash the organic phase with saturated sodiumhydrogen carbonate solution, dry over anhydrous magnesium sulfate andconcentrate. Purify by silica gel chromatography (400 mL silica gel, 20%ethyl acetate/heptane as eluent) to give the title compound (4.6 g,68%).

Step F: Preparation of[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, diethyl ester

Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid, ethyl ester (6.5 g,28 mmol) and diethylcarbonate (4.0 g, 34 mmol) in tetrahydrofuran (100mL). Add 62 mL (62 mmol) of a 1.0 molar solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran over 0.5 hours. Stir 28hours. Add iodomethane (5.3 g, 35 mmol). Stir 2 days. Add water andethyl acetate. Wash organic phase with brine, dry over anhydrousmagnesium sulfate and concentrate. Purify by flash chromatography (200 gsilica gel, ethyl acetate/heptane as eluent) to give the title compound(1.43 g, 17%).

Step F: Preparation of[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dimethyl ester

Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid, methyl ester (1.5 g,6.0 mmol) and dimethylcarbonate (930 mg, 10.3 mmol) in tetrahydrofuran(10 mL). Add 20 mL (20 mmol) of a 1.0 molar solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran over 0.5 hours. Stir 3 days.Add iodomethane (5.3 g, 35 mmol). Stir 24 hours. Add water and ethylacetate. Wash organic phase with brine, dry over anhydrous magnesiumsulfate and concentrate. Purify by flash chromatography (50 g silicagel, ethyl acetate/heptane as eluent) to give the title compound (315mg, 16%).

Additionally, the following compounds can be prepared by the syntheticprocedure depicted in Step F:

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, ethyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, methyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, butyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, methyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, hexyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, ethyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, butyl ethyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, ethyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, ethyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dipropyl ester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, butyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, pentyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, hexyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dibutyl ester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, butyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, butyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dipentyl ester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, hexyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dihexyl ester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, diethyl ester

[4-(cyclopropylcarbonyl)phenylethyl-propanedioic acid, dimethyl ester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, ethyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, methyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, butyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, methyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, hexyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, ethyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, butyl ethyldiester

[4-(cyclopropylcarbonyl)phenylethyl-propanedioic acid, ethyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, ethyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, dipropyl ester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, butyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, pentyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, hexyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, dibutyl ester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, butyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, butyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, dipentyl ester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, hexyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, dihexyl ester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, diethyl ester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, dimethyl ester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, ethyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, methyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, butyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, methyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, hexyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, ethyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, butyl ethyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, ethyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, ethyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, dipropyl ester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, butyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, pentyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, hexyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, dibutyl ester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, butyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, butyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, dipentyl ester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, hexyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, dihexyl ester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, diethyl ester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, dimethyl ester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, ethyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, methyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, butyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, methyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, hexyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, ethyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, butyl ethyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, ethyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, ethyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, dipropyl ester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, butyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, pentyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, hexyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, dibutyl ester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, butyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, butyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, dipentyl ester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, hexyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]butyl-propanedioic acid, dihexyl ester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, diethyl ester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, dimethyl ester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, ethyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, methyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, butyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, methyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, hexyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, ethyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, butyl ethyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, ethyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, ethyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, dipropyl ester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, butyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, pentyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, hexyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, dibutyl ester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, butyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, butyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, dipentyl ester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, hexyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]pentyl-propanedioic acid, dihexyl ester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, diethyl ester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, dimethyl ester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, ethyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, methyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, butyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, methyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, hexyl methyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, ethyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, butyl ethyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, ethyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, ethyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, dipropyl ester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, butyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, pentyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, hexyl propyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, dibutyl ester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, butyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, butyl hexyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, dipentyl ester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, hexyl pentyldiester

[4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, dihexyl ester

Step G: Preparation of[4-(4-chloro-1-oxobutyl)phenyl]methyl-propanedioic acid, diethyl ester

Bubble hydrogen chloride gas through a solution of[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, diethyl ester(570 mg, 2.0 mmol) in ethanol (4 mL) for 5 minutes. Heat the solution toreflux. After 18 hours, cool the solution to room temperature and bubblenitrogen through the solution for 1 hour. Add ethyl acetate and water tothe residue. Dry the organic phase over anhydrous magnesium sulfate andconcentrate. Dissolve the crude product in ethanol (50 mL) and bubblehydrogen chloride gas through the solution for 10 minutes. Heat thesolution to reflux. After stirring 2 days, concentrate the solution. Addwater and ethyl acetate to the residue. Dry the organic phase overanhydrous magnesium sulfate and concentrate. Purify by flashchromatography (150 g silica gel, 20% ethyl acetate/heptane as eluent)to give the title compound (409 mg, 59%).

Step G: Preparation of[4-(4-chloro-1-oxobutyl)phenyl]methyl-propanedioic acid, dimethyl ester

Bubble hydrogen chloride gas through a solution of[4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dimethyl ester(315 mg, 1.1 mmol) in ethanol (3 mL) and toluene (9 mL) for 10 minutes.Heat the solution to 68° C. After 4 hours, cool the solution to roomtemperature and bubble nitrogen through the solution for 1 hour. Addethyl acetate and water to the residue. Dry the organic phase overanhydrous magnesium sulfate and concentrate to give the title compound(321 mg, 91%).

Additionally, the following compounds can be prepared by the syntheticprocedure depicted in Step G:

[4-(4-bromo-1-oxobutyl)phenyl]methyl-propanedioic acid, diethyl ester

[4-(4-iodo-1-oxobutyl)phenyl]methyl-propanedioic acid, diethyl ester

[4-(4-bromo-1-oxobutyl)phenyl]methyl-propanedioic acid, dimethyl ester

[4-(4-iodo-1-oxobutyl)phenyl]methyl-propanedioic acid, dimethyl ester

Furthermore, compounds derived from all permutations of substituents asset forth in the illustrative examples following Step F can be preparedby the synthetic procedure depicted in Step G.

Step H: Preparation of[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]methyl-propanedioicacid, diethyl ester

Mix together [4-(4-chloro-1-oxobutyl)phenyl]methyl-propanedioic acid,diethyl ester (380 mg, 1.1 mmol), potassium carbonate (450 mg, 3.2mmol), α-(4-pyridyl)benzhydrol (500 mg, 1.9 mmol), water (4 mL) andtoluene (10 mL). Heat the mixture to reflux. After 7 days, cool to roomtemperature. Add ethyl acetate and water. Wash the organic phase withbrine, dry over anhydrous magnesium sulfate and concentrate. Purify byflash chromatography (200 g of silica gel, 10% methanol/chloroform aseluent) to give the title compound (627 mg, 99%).

Step H: Preparation of[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]methyl-propanedioicacid, dimethyl ester

Mix together [4-(4-chloro-1-oxobutyl)phenyl]methyl-propanedioic acid,dimethyl ester (300 mg, 0.92 mmol), potassium carbonate (350 mg, 2.5mmol), α-(4-pyridyl)benzhydrol (500 mg, 1.9 mmol), water (3 mL) andtoluene (7 mL). Heat the mixture to reflux. After 5 days, cool to roomtemperature. Add ethyl acetate and water. Wash the organic phase withbrine, dry over anhydrous magnesium sulfate and concentrate. Purify byflash chromatography (150 g of silica gel, 10% methanol/chloroform aseluent) to give the title compound (387 mg, 76%). Additionally,compounds derived from all permutations of substituents as set forth inthe illustrative examples following Step F can be prepared by thesynthetic procedure depicted in Step H.

Step I: Preparation of4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneaceticacid, ethyl ester

Dissolve[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]methyl-propanedioicacid, diethyl ester (515 mg, 0.88 mmol) in tetrahydrofuran (5 mL) andcool the solution with an ice bath. Add lithiumtri-tert-butoxyaluminohydride (10 mL of a 1 molar solution intetrahydrofuran, 10 mmol) portionwise over 20 minutes. After 2 hours,allow the solution to warm to room temperature. After 48 hours, cool thesolution with an ice bath and add a 10% potassium hydrogen sulfateaqueous solution (10 mL). Wash the organic phase with brine, dry overanhydrous magnesium sulfate, and concentrate. Purify by flashchromatography (150 g of silica gel, 5% methanol/chloroform as eluent)to give the compound (321 mg, 67%).

Additionally, the following compounds can be prepared by the syntheticprocedure depicted in Step 1:

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneaceticacid, methyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneaceticacid, propyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneaceticacid, butyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneaceticacid, pentyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneaceticacid, hexyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-ethyl-benzeneaceticacid, methyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-ethyl-benzeneaceticacid, ethyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-ethyl-benzeneaceticacid, propyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-ethyl-benzeneaceticacid, butyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-ethyl-benzeneaceticacid, pentyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-ethyl-benzeneaceticacid, hexyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-propyl-benzeneaceticacid, methyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-propyl-benzeneaceticacid, ethyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-propyl-benzeneaceticacid, propyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-propyl-benzeneaceticacid, butyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-propyl-benzeneaceticacid, pentyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-propyl-benzeneaceticacid, hexyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-butyl-benzeneaceticacid, methyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-butyl-benzeneaceticacid, ethyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-butyl-benzeneaceticacid, propyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-butyl-benzeneaceticacid, butyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-butyl-benzeneaceticacid, pentyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-butyl-benzeneaceticacid, hexyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-pentyl-benzeneaceticacid, methyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-pentyl-benzeneaceticacid, ethyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-pentyl-benzeneaceticacid, propyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-pentyl-benzeneaceticacid, butyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-pentyl-benzeneaceticacid, pentyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-pentyl-benzeneaceticacid, hexyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-hexyl-benzeneaceticacid, methyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-hexyl-benzeneaceticacid, ethyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-hexyl-benzeneaceticacid, propyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-hexyl-benzeneaceticacid, butyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-hexyl-benzeneaceticacid, pentyl ester

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-hexyl-benzeneaceticacid, hexyl ester

Step J: Preparation of4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneaceticacid

Dissolve4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneaceticacid, ethyl ester (200 mg, 0.37 mmol) in methanol (8 mL) andtetrahydrofuran (12 mL). Add 1.6 mL (1.6 mmol) of a 1 molar solution ofaqueous sodium hydroxide. After 4 hours, cool the solution to roomtemperature and add 10% hydrochloric acid (ca. 1 mL) dropwise until pHis 5-6. Concentrate the solution and purify by flash chromatography (50g of silica gel, methanol/chloroform gradient elution) to give the titlecompound (127 mg, 66%).

Additionally, the following compounds can be prepared by the syntheticprocedure depicted in Step J:

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-ethyl-benzeneaceticacid

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-propyl-benzeneaceticacid

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-butyl-benzeneaceticacid

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-pentyl-benzeneaceticacid

4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-hexyl-benzeneaceticacid

EXAMPLES OF SYNTHESIS SET FORTH IN SCHEME B

To a slurry of AlCl₃ (210 g, 1.6 mol) in methylene chloride (200 mL)cooled in an ice bath is added 4-chlorobutyryl chloride (121 g) dropwisewhile maintaining the pot temperature below 10° C. After 10 minutes,ethyl benzeneacetic acid (118 g, 0.72 mol) is added dropwise maintainingthe pot temperature below 10° C. The mixture is stirred at roomtemperature for 1 hour, then heated to 40° C. After 4 hours, thesolution is cooled to room temperature and poured onto crushed ice (2L). Methylene chloride (1 L) is added. The organic phase is separated.The aqueous phase is extracted with two 1 L portions of methylenechloride. The combined organics are dried (MgSO₄) and concentrated.Toluene (1 L) is added and the solution is concentrated to ca. 500 mL.Ethanol (500 mL) is added. The solution is heated to 70° C. and HCl (g)is bubbled through for 20 minutes. The solution is sparged with N₂ andconcentrated. Chromatography through silica gel (2.5 L) using an ethylacetate/heptane gradient gives a 1:1 mixture of meta, para ethyl(4-chloro-1-oxobutyl)benzene acetic acid (119 g). To a slurry of LiOH(23.5 g, 0.56 mol) in water (100 mL) and ethanol (100 mL) is added the1:1 mixture of meta, para ethyl (4-chloro-1-oxobutyl)benzene acetic acid(50 g, 0.19 mol). The reaction becomes exothermic and is cooled with anice bath. After 1 hour, the solution is allowed to warm to roomtemperature. After 18 hours, the mixture is concentrated. Water (400 mL)and conc. HCl are added (until pH 4). Ethyl acetate (600 mL) is added.The organic phase is separated, washed with brine and dried (MgSO4). Thesolution is heated on a steam bath and charcoal (ca. 3 g) is added. Themixture is filtered through Celite and concentrated. The residue isdissolved in ethyl acetate (300 mL) and heptane (600 mL) with heating.Seed crystals are added. After cooling an organic oil appears. Heptane(500 mL) is added and the mixture is heated to reflux, treated withcharcoal (ca. 5 g), filtered and seeded. A solid forms and is collected.¹H NMR shows ca. 4:1 mixture of para:meta isomers. Recrystallizationfrom ethyl acetate/heptane gives 4 (cyclopropylcarbonyl)benzeneaceticacid (4.3g, 11%).

EXAMPLES OF SYNTHESIS AS SET FORTH IN SCHEME C

Step a: Preparation of 4-(cyclopropylcarbonyl) benzeneacetic acid, ethylester

See preparation under Step E, Scheme A, disclosed previously herein.

Step b: Preparation of[4-(cyclopropylcarbonyl)]-α-α-dimethylbenzeneacetic acid, ethyl ester

In a 2 L, glass, jacketed reactor is loaded the 4-(cyclopropylcarbonyl)benzeneacetic acid, ethyl ester (232 g, 1 mole), diglyme (150 mL) andmethyl chloride (127 g, 2.5 mole). In a heated addition vessel is loadedpotassium tert-butoxide (182.4 g, 1.6 mole) and diglyme (1050 mL). Thejacket for the reactor is set at −10° C. and the addition vesselcontents are heated to 60° C. The base solution is added to the reactorat a rate which keeps the internal temperature of the reaction below 25°C. After the base addition, sodium ethoxide as a 21% solution in ethanol(86 g, 0.3 mole) is added to quench any excess methyl chloride. Theentire reaction mixture is then agitated with toluene (900 mL) and water(1200 mL) containing sodium bicarbonate (8.4 g). The phases areseparated and the organic layer is washed with additional water (200 mL)to remove any residual potassium chloride salts. Without phaseseparating, the entire solution is then acidified to pH=3 withconcentrated HCl. The organic is then stripped of solvents to afford thetitle compound.

Step c: Preparation of 4-(4-chloro-1-oxobuty)-α,α-dimethylbenzeneaceticacid, ethyl ester

To a 4 L reactor equipped with a gas inlet, overhead stirrer andtemperature control, is charged[4-(cyclopropylcarbonyl)]-α,α-dimethylbenzeneacetic acid, ethyl ester(500 g). The oil is heated to 60° C. and the head space is evacuated.HCl is then added raising the pressure to 10 psig. After 4 hours, theexcess HCl is vented and the oil is sparged with nitrogen for 5 minutes.

Step d: Preparation of Ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α-α-dimethylbenzeneacetatehydrochloride

According to the described procedure of Carr et al., U.S. Pat. No.4,254,129, a mixture of 4.5 g (0.0163 mole) ofα,α-diphenyl-4-piperidemethanol, 6.1 g (0.0205 mole) of ethyl4-(4-chloro-1-oxobuty)-α,α-dimethylphenylacetate, 5 g (0.05 mole) ofpotassium bicarbonate and 0.05 g of potassium iodide in 50 ml of tolueneis stirred and refluxed for 72 hours then filtered. Ether then etherealhydrogen chloride is added to the filtrate, and the resultingprecipitate collected and recrystallized several times frommethanol-butanone and butanone to give ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetatehydrochloride. M.P.205.5°-208° C.

Step e: Preparation of Ethyl4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate

According to the described procedure of Carr et al., U.S. Pat. No.4,254,129, a solution of 5.64 g (0.01 mole) of ethyl4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetatehydrochloride in 200 ml of absolute ethanol and 50 ml of methanol and0.5 g of platinum oxide is hydrogenated at about 50 psi for about 1 houruntil the infrared shows no evidence of a ketone carbonyl function. Thesolution is filtered and the filtrate concentrated leaving a residuewhich is recrystallized from butanone and methanol-butanone to giveethyl4-[4[4-(hydroxydiphenylmethyl)-1-peperidinyl]-1-hydroxybuty]-α,α-dimethylbenzeneacetateHCl, M.P.185°-187° C.

Step f:4-[4[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid

According to the described procedure of Carr et al., U.S. Pat. No.4,254,129, to a solution of 0.6 g of ethyl4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-hydroxybutyl]-α,α-dimethylbenzeneacetatein 20 ml of absolute ethanol is added 10 ml of a 50% solution of sodiumhydroxide. The mixture is refluxed for 3½ hours and concentrated to asolid after which a minimum amount of methanol to dissolve the residueis added. 10% Aqueous HCl is added until pH 7 is reached, the methanolremoved by evaporation and water (25 ml) is added. The resultingprecipitate is recrystallized from methanolbutanone to give4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid, M.P. 195°-197° C.

The piperidine derivative of formula (I) is used according to thepresent invention as a histamine H₁-receptor antagonist and as such willprovide relief of symptoms associated with histamine-mediated allergicdisorders in patients suffering therefrom. Histamine-mediated allergicdisorders are diseases or conditions which have a histamine-mediatedallergic component such as, for example, seasonal allergic rhinitis,perennial rhinitis, idiopathic urticaria, asthma and the like. Relief ofsymptoms of an allergic disorder by treatment according to the presentinvention refers to a decrease in symptom severity over that expected inthe absence of treatment and does not necessarily indicate a totalelimination of the disease.

Antihistaminic potential is measured by affinity of a test compound for[³H] pyrilamine binding sites associated with the antagonist componentof H₁-histaminergic receptors in animal brain membranes. Affinity forthis receptor is indicative of the potential of a test compound tointeract with central and peripheral H₁-histaminergic receptors.

The following method is used to determine the affinity of test compoundsfor [³H] pyrilamine binding sites in rat cortex.

The brains of young male rats are removed. The cortici are dissected andstored at −20° C. or immediately used. The tissue is homogenized in 10ml of ice-cold 50 nM K/NaPO₄ buffer (pH 7.4) using a Polytron (setting 6for 15 seconds). The homogenate is centrifuged at 40,000 g for 15minutes at 4° C. The pellet is resuspended in the same buffer in orderto have 100 mg wet weight/ml buffer. The incubation tubes contain 50 mMK/NaPO₄ buffer, promethazine (2.10-6 M final) or test compound, ³Hpyrilamine (2 nM final) and homogenate (10 mg wet weight per tube) in afinal volume of 250-1000 ml. After a 30 minute incubation at roomtemperature each incubation is terminated by rapid filtration throughWhatman GF/B glass fiber filters, presoaked in water when using aBrandel cell harvester, or used as such when the filtration is performedwith a 96 well Skatron cell harvester. The filters are rinsed with 3×3ml 0.9% NaCl (Brandel) or prewetted and rinsed for 10 sec with NaCl(Skatron). The filters are either transferred to scintillation vials and10 ml Quicksafe A is added for liquid scintillation spectrometry or athin layer of solid scintillant is melted onto the filters and thefilters then counted using a betaplate beta counter. Specific binding of³H pyrilamine is measured as the excess over blanks taken in thepresence of 2.10-6 M promethazine. Protein content of the membranes isdetermined by the method of Lowry et al., J. Biol. Chem. 193, 265-275(1951). Displacement curves are analyzed using the GraphPad (GraphPadSoftware, Inc.) or similar program to obtain Hill slopes and IC₅₀values. The K_(i) value is then determined with the Cheng-Prusoffequation described by Cheng et al., in Biochem. Pharmacol., 22,3099-3108 (1973), using the K_(D) for ³H pyrilamine as obtained fromprevious saturation experiments performed under the same conditions.

The K_(i) for4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneacetic acid is 3.6×10⁻⁷ indicating that the piperidinederivative of formula (I) is useful for the treatment ofhistamine-mediated allergic disorders.

As used herein, the term “patient” refers to an adult person who issuffering from a histamine-mediated allergic disorder. It is understoodthat for purposes of the present invention, the term “adult” refers to aperson of 12 years of age or older who would typically be treated forallergic disorders with an antihistamine dosage as recommended foradults.

The identification of those patients who would benefit from the presentinvention is well within the ability and knowledge of one skilled in theart. A clinician skilled in the art can readily identify, by the use ofclinical tests, physical examination and medical/family history, thosepatients who are suffering from an allergic disorder that ishistamine-mediated.

The quantity of novel compound administered will vary depending on themode of administration and can be any effective antiallergic amount. Thequantity of novel compound administered may vary over a wide range toprovide in a unit dosage an effective amount of from about 0.01 to 20mg/kg of body weight of the patient per day to achieve the desiredeffect. For example, the desired antihistamine, antiallergy andbronchodilator effects can be obtained by administering the piperidinecompound of formula (I) to a patient in a daily amount of from about 10mg to about 50 mg. A preferred daily dose is from about 20 mg to about40 mg. The most preferred daily dose is about 30 mg.

It is of course understood that the daily dose may be administered to apatient according to a dosage regimen in single or multiple dosageunits. For example, a daily dose may be administered in a regimenrequiring one, two, three, or four unit doses. Typically, these unitdoses will be of equal strength and will be administered on a timeschedule so that each dose is approximately equally spaced throughoutthe day. For example, a daily dose requiring a once a day dosage regimenmay be administered about every 24 hours; a daily dose requiring atwice-α-day dosage regimen may be administered about every 12 hours; adaily dose requiring a three times-a-day dosage regimen may beadministered about every 8 hours; a daily dose requiring a fourtimes-a-day dosage regimen may be administered about every 6 hours.

The piperidine derivative of formula (I) can be administered accordingto the present invention in any form or mode which makes the compoundbioavailable in effective amounts, including oral and parenteral routes.For example, the piperidine derivative of formula (I) can beadministered orally, subcutaneously, transdermally, intranasally, andthe like. Oral administration is preferred. One skilled in the art ofpreparing formulations can readily select the proper form and mode ofadministration depending upon the particular characteristics of thecompound selected, the disease state to be treated, the stage of thedisease, and other relevant circumstances.

The compounds can be administered alone or in the form of apharmaceutical composition with pharmaceutically acceptable carriers orexcipients, the proportion and nature of which are determined by thechosen route of administration and standard pharmaceutical practice. Thepiperidine derivative of formula (I), while effective itself, may beformulated and administered in the form of its pharmaceuticallyacceptable acid addition salt for purposes of stability, convenience ofcrystallization, increased solubility and the like. In addition, anindividual polymorph, solvate, or individual stereoisomer of thepiperidine derivative of formula (I) [i.e.,(R,R)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneacetic acid;(R,S)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methylbenzeneacetic acid;(S,S)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneaceticacid and (S,R)-4-[1hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-α-methyl-benzeneaceticacid] may be used.

The present invention contemplates compositions comprising thepiperidine derivative of formula (I) in admixture or otherwise inassociation with one or more inert carriers. These compositions areuseful, for example, as assay standards, as convenient means of makingbulk shipments, or as pharmaceutical compositions. An assayable amountof the piperidine derivative of formula (I) is an amount which isreadily measurable by standard assay procedures and techniques as arewell known and appreciated by those skilled in the art. Assayableamounts of the piperidine derivative of formula (I) will generally varyfrom about 0.001% to about 75% of the composition by weight. Inertcarriers can be any material which does not degrade or otherwisecovalently react with the piperidine derivative of formula (I). Examplesof suitable inert carriers are water; aqueous buffers, such as thosewhich are generally useful in High Performance Liquid Chromatography(HPLC) analysis organic solvents, such as acetonitrile, ethyl acetate,hexane and the like; and pharmaceutically acceptable carriers orexcipients.

More particularly, the present invention contemplates a pharmaceuticalcomposition in solid unit dosage form comprising an amount of thepiperidine derivative of formula (I) from about 15 mg to about 30 mg inadmixture with a pharmaceutically acceptable carrier. As used herein,the term “solid unit dosage form” contemplates a solid dosage form fororal administration such as a tablet, capsule, and the like, as well assolid dosage forms for parenteral administration such as a transdermalpatch, and the like.

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material which can serve as a vehicle or mediumfor the active ingredient. Suitable carriers or excipients are wellknown in the art. The pharmaceutical composition may be adapted for oralor parenteral use and may be administered to the patient in the form oftablets, capsules, solutions, suspensions, transdermal patch, and thelike.

The piperidine derivative of formula (I) may be administered orally, forexample, with an inert diluent or with an edible carrier. It may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the piperidine derivative of formula(I) may be incorporated with excipients and used in the form of tablets,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 4% of the compound ofthe invention, the active ingredient, but may be varied depending uponthe particular form and may conveniently be between about 4% to about70% of the weight of the unit. The amount of the compound present incompositions is such that a suitable dosage will be obtained uponadministration. Preferred compositions and preparations according to thepresent invention are prepared so that an oral unit dosage form containsbetween about 15 mg to about 30 mg. Most preferred unit doses for oraladministration are those which contain about 15 mg to about 30 mg.

The tablets, pills, capsules, and the like may also contain one or moreof the following adjuvants: binders such as microcrystalline cellulose,gum tragacanth or gelatin; excipients such as starch or lactose,disintegrating agents such as alginic acid, Primogel™, corn starch,carbonate salts such as sodium bicarbonate or calcium carbonate, and thelike; lubricants such as magnesium stearate or Sterotex™; glidents suchas colloidal silicon dioxide; and sweetening agents such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as polyethylene glycol or a fatty oil. Other dosage unitforms may contain other various materials which modify the physical formof the dosage unit, for example, as coatings. Thus, tablets or pills maybe coated with sugar, shellac, or other enteric coating agents. A syrupmay contain, in addition to the present compounds, sucrose as asweetening agent and certain preservatives, dyes and colorings andflavors. Materials used in preparing these various compositions shouldbe pharmaceutically pure and non-toxic in the amounts used. Preferredexcipients are corn starch, gelatin, lactose, magnesium stearate andsodium bicarbonate.

Oral unit dosage forms may be formulated to provide immediate orsustained release characteristics. These forms may be formulatedaccording to conventional techniques and procedures to give thedesirable dissolution and bioavailability characteristics.

In addition, the piperidine derivative of formula (I) may beincorporated into a solution or suspension for oral or parenteraladministration. These preparations should contain at least 0.1% of thepiperidine derivative of formula (I), but may be varied to be between0.1 and about 50% of the weight thereof. The amount of the piperidinederivative of formula (I) in such compositions is such that a suitabledosage will be obtained upon oral or parenteral administration.

The solutions or suspensions may also include the one or more of thefollowing adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose.

Transdermal dosage forms for administering the piperidine derivative offormula (I) can be prepared by conventional techniques well known in theart of pharmaceutical science such as by incorporating the piperidinederivative of formula (I) into various polymeric reservoir matrixmaterials. These polymeric matrix materials may include pressuresensitive acrylic, silicone, polyurethane, ethylene vinyl acetatecopolymers, polyolefins, and rubber adhesive matrices, medical gradesilicone fluids, and medical grade silicone elastamers, which are wellknown in the art for forming reservoirs for transdermal delivery ofdrugs.

It is further contemplated that the piperidine derivative of formula (I)according to the present invention, may be formulated with a variety ofother active ingredients which are commonly combined withantihistamines, such as a decongestant, including pseudoephedrine andthe like; analgesics such as acetaminophen and the like, non-steroidalanti-inflammatory agents such as ibuprofen and the like.

What is claimed is:
 1. A compound of the formula

wherein R₁ is H or C₁-C₆alkyl and the C₁-C₆alkyl moiety is straight orbranched; R₂ and R₃ are each independently C₁-C₆alkyl and the C₁-C₆alkylmoiety is straight or branched; or stereoisomers or pharmaceuticallyacceptable acid addition salt thereof.
 2. The compound of claim 1wherein R₁ is methyl and R₂ and R₃ are ethyl.